The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Joseph J. Volpe - One of the best experts on this subject based on the ideXlab platform.
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Development/Plasticity/Repair Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role
2016Co-Authors: For Topiramate, Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Weimin Dai, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA – kainate-type glutamate receptor blockade in a rodent model of Periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for Periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA – kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligoden-drocytes, similar to the AMPA – kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, pro-tective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA – kainate receptor blockade may have potential for translation as a therapeutic strategy for Periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter. Key words: white matter; glutamate receptor; Periventricular Leukomalacia; topiramate; oligodendrocyte; excitotoxicit
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neuron deficit in the white matter and subplate in Periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Robin L Haynes, Rebecca D Folkerth, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with Periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
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the cerebral cortex overlying Periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Saraid S Billiards, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by Periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
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nitrosative stress and inducible nitric oxide synthase expression in Periventricular Leukomalacia
Acta Neuropathologica, 2009Co-Authors: Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the Periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.
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thalamic damage in Periventricular Leukomalacia novel pathologic observations relevant to cognitive deficits in survivors of prematurity
Pediatric Research, 2009Co-Authors: Poonam Ligam, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Lena Liu, May Yang, Hannah C KinneyAbstract:Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30–50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular Leukomalacia (PVL), characterized by Periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7–10). We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e., mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5±4.8 weeks) and 16 non-PVL controls (36.7±5.2 weeks) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared to controls (19%; 3/16)(p=0.01), with substantial involvement of the mediodorsal and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
Hannah C Kinney - One of the best experts on this subject based on the ideXlab platform.
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neuron deficit in the white matter and subplate in Periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Robin L Haynes, Rebecca D Folkerth, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with Periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
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the cerebral cortex overlying Periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Saraid S Billiards, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by Periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
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nitrosative stress and inducible nitric oxide synthase expression in Periventricular Leukomalacia
Acta Neuropathologica, 2009Co-Authors: Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the Periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.
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thalamic damage in Periventricular Leukomalacia novel pathologic observations relevant to cognitive deficits in survivors of prematurity
Pediatric Research, 2009Co-Authors: Poonam Ligam, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Lena Liu, May Yang, Hannah C KinneyAbstract:Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30–50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular Leukomalacia (PVL), characterized by Periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7–10). We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e., mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5±4.8 weeks) and 16 non-PVL controls (36.7±5.2 weeks) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared to controls (19%; 3/16)(p=0.01), with substantial involvement of the mediodorsal and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
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diffuse axonal injury in Periventricular Leukomalacia as determined by apoptotic marker fractin
Pediatric Research, 2008Co-Authors: Robin L Haynes, Joseph J. Volpe, Saraid S Billiards, Natalia S Borenstein, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [β-amyloid precursor protein (β-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using β-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.
Rebecca D Folkerth - One of the best experts on this subject based on the ideXlab platform.
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neuron deficit in the white matter and subplate in Periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Robin L Haynes, Rebecca D Folkerth, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with Periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
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the cerebral cortex overlying Periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Saraid S Billiards, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by Periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
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nitrosative stress and inducible nitric oxide synthase expression in Periventricular Leukomalacia
Acta Neuropathologica, 2009Co-Authors: Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the Periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.
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thalamic damage in Periventricular Leukomalacia novel pathologic observations relevant to cognitive deficits in survivors of prematurity
Pediatric Research, 2009Co-Authors: Poonam Ligam, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Lena Liu, May Yang, Hannah C KinneyAbstract:Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30–50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular Leukomalacia (PVL), characterized by Periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7–10). We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e., mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5±4.8 weeks) and 16 non-PVL controls (36.7±5.2 weeks) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared to controls (19%; 3/16)(p=0.01), with substantial involvement of the mediodorsal and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
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myelin abnormalities without oligodendrocyte loss in Periventricular Leukomalacia
Brain Pathology, 2008Co-Authors: Saraid S Billiards, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Natalia S Borenstein, David H Rowitch, Keith L Ligon, Hannah C KinneyAbstract:The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of Periventricular Leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the Periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.
Frances E Jensen - One of the best experts on this subject based on the ideXlab platform.
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Development/Plasticity/Repair Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role
2016Co-Authors: For Topiramate, Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Weimin Dai, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA – kainate-type glutamate receptor blockade in a rodent model of Periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for Periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA – kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligoden-drocytes, similar to the AMPA – kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, pro-tective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA – kainate receptor blockade may have potential for translation as a therapeutic strategy for Periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter. Key words: white matter; glutamate receptor; Periventricular Leukomalacia; topiramate; oligodendrocyte; excitotoxicit
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Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of Periventricular Leukomalacia.
Pediatric research, 2015Co-Authors: Lauren L. Jantzie, Hyun-kyung Park, Michele Jackson, Jessie R. Maxwell, Frances E JensenAbstract:Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of Periventricular Leukomalacia
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role of glutamate receptors in Periventricular Leukomalacia
Journal of Child Neurology, 2005Co-Authors: Frances E JensenAbstract:Periventricular Leukomalacia is a form of white-matter injury that occurs in the setting of either primary or secondary hypoxia-ischemia in the premature infant. Hypoxia-ischemia induces increases in cerebral extracellular glutamate levels, thereby activating glutamate receptors on a variety of cell types within the white matter. This review examines the evidence of a role for glutamate receptors in white-matter injury and Periventricular Leukomalacia. Multiple glutamate receptor subtypes exist, and these appear to play differential roles depending on cell type and time after injury. Glutamate receptors are developmentally regulated on neurons and glia, and certain subtypes are transiently overexpressed in developing rodent brain and are expressed on immature oligodendrocytes in human white matter in the premature period. Pharmacologic agents acting on glutamate receptors might represent age-specific therapeutic strategies for the treatment of Periventricular Leukomalacia.
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glutamate receptor mediated oligodendrocyte toxicity in Periventricular Leukomalacia a protective role for topiramate
The Journal of Neuroscience, 2004Co-Authors: Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of Periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for Periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo , is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro . Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for Periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.
Robin L Haynes - One of the best experts on this subject based on the ideXlab platform.
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neuron deficit in the white matter and subplate in Periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Robin L Haynes, Rebecca D Folkerth, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with Periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
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the cerebral cortex overlying Periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Saraid S Billiards, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by Periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
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nitrosative stress and inducible nitric oxide synthase expression in Periventricular Leukomalacia
Acta Neuropathologica, 2009Co-Authors: Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Felicia L Trachtenberg, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the Periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.
-
thalamic damage in Periventricular Leukomalacia novel pathologic observations relevant to cognitive deficits in survivors of prematurity
Pediatric Research, 2009Co-Authors: Poonam Ligam, Joseph J. Volpe, Robin L Haynes, Rebecca D Folkerth, Lena Liu, May Yang, Hannah C KinneyAbstract:Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30–50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular Leukomalacia (PVL), characterized by Periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7–10). We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e., mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5±4.8 weeks) and 16 non-PVL controls (36.7±5.2 weeks) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared to controls (19%; 3/16)(p=0.01), with substantial involvement of the mediodorsal and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
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diffuse axonal injury in Periventricular Leukomalacia as determined by apoptotic marker fractin
Pediatric Research, 2008Co-Authors: Robin L Haynes, Joseph J. Volpe, Saraid S Billiards, Natalia S Borenstein, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [β-amyloid precursor protein (β-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using β-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.